rs3802805
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
The NM_021926.4(ALX4):c.1074C>T(p.His358=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,612,836 control chromosomes in the GnomAD database, including 101,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.31 ( 8218 hom., cov: 33)
Exomes 𝑓: 0.35 ( 93155 hom. )
Consequence
ALX4
NM_021926.4 synonymous
NM_021926.4 synonymous
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 2.55
Genes affected
ALX4 (HGNC:450): (ALX homeobox 4) This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 11-44265016-G-A is Benign according to our data. Variant chr11-44265016-G-A is described in ClinVar as [Benign]. Clinvar id is 304701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44265016-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=2.55 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALX4 | NM_021926.4 | c.1074C>T | p.His358= | synonymous_variant | 4/4 | ENST00000652299.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALX4 | ENST00000652299.1 | c.1074C>T | p.His358= | synonymous_variant | 4/4 | NM_021926.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.307 AC: 46686AN: 152044Hom.: 8203 Cov.: 33
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GnomAD3 exomes AF: 0.373 AC: 93097AN: 249426Hom.: 19228 AF XY: 0.369 AC XY: 49992AN XY: 135324
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GnomAD4 exome AF: 0.350 AC: 511825AN: 1460674Hom.: 93155 Cov.: 72 AF XY: 0.351 AC XY: 254850AN XY: 726672
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GnomAD4 genome ? AF: 0.307 AC: 46736AN: 152162Hom.: 8218 Cov.: 33 AF XY: 0.313 AC XY: 23267AN XY: 74360
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Parietal foramina 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2018 | - - |
Frontonasal dysplasia with alopecia and genital anomaly Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at